Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions

Canada's Patented Medicine Notice of Compliance regulations: balancing the scales or tipping them?

<p>Abstract</p> <p>Background</p> <p>In order to comply with the provisions of the North American Free Trade Agreement, in 1993 the Canadian federal government introduced the Patented Medicine Notice of Compliance Linkage Regulations. These regulations were meant to achieve a balance between the timely entry of generic medicines and the rights of patent holders. The regulations tied the regulatory approval of generic medicines to the patent status of the original brand-name product.</p> <p>Discussion</p> <p>Since their introduction the regulations have been a source of contention between the generic and the brand-name industry. While the regulations have generated a considerable amount of work for the Federal Court of Canada both sides dispute the interpretation of the "win rate" in the court cases. Similarly, there is no agreement on whether multiple patents on single drugs represent a legitimate activity by the brand-name industry or an "evergreening" tactic. The generic industry's position is that the regulations are being abused leading to the delay in the introduction of lower cost generic products by as much as 8 years. The brand-name companies counter that the regulations are necessary because injunctions against the introduction of generic products are frequently unavailable to them. The regulations were amended in 2006 and again in 2008 but both sides continue to claim that the regulations favour the other party. The battle around the regulations also has an international dimension with interventions by PhRMA, the trade association representing the United States based multinational companies, arguing that the regulations are not stringent enough and that Canada needs to be placed on the U.S. Priority Watch List of countries. Finally, there are multiple costs to Canadian society as a result of the NOC regulations.</p> <p>Summary</p> <p>Despite the rhetoric there has been almost no empiric academic research done into the effect of the regulations. In order to develop rational policy in this area a number of key research questions have been formulated.</p

Atrazine and Breast Cancer: A Framework Assessment of the Toxicological and Epidemiological Evidence

The causal relationship between atrazine exposure and the occurrence of breast cancer in women was evaluated using the framework developed by Adami et al. (2011) wherein biological plausibility and epidemiological evidence were combined to conclude that a causal relationship between atrazine exposure and breast cancer is “unlikely”. Carcinogenicity studies in female Sprague-Dawley (SD) but not Fischer-344 rats indicate that high doses of atrazine caused a decreased latency and an increased incidence of combined adenocarcinoma and fibroadenoma mammary tumors. There were no effects of atrazine on any other tumor type in male or female SD or Fischer-344 rats or in three strains of mice. Seven key events that precede tumor expression in female SD rats were identified. Atrazine induces mammary tumors in aging female SD rats by suppressing the luteinizing hormone surge, thereby supporting a state of persistent estrus and prolonged exposure to endogenous estrogen and prolactin. This endocrine mode of action has low biological plausibility for women because women who undergo reproductive senescence have low rather than elevated levels of estrogen and prolactin. Four alternative modes of action (genotoxicity, estrogenicity, upregulation of aromatase gene expression or delayed mammary gland development) were considered and none could account for the tumor response in SD rats. Epidemiological studies provide no support for a causal relationship between atrazine exposure and breast cancer. This conclusion is consistent with International Agency for Research on Cancer’s classification of atrazine as “unclassifiable as to carcinogenicity” and the United States Environmental Protection Agency's classification of atrazine as “not likely to be carcinogenic.

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

'Linkage' pharmaceutical evergreening in Canada and Australia

'Evergreening' is not a formal concept of patent law. It is best understood as a social idea used to refer to the myriad ways in which pharmaceutical patent owners utilise the law and related regulatory processes to extend their high rent-earning intellectual monopoly privileges, particularly over highly profitable (either in total sales volume or price per unit) 'blockbuster' drugs. Thus, while the courts are an instrument frequently used by pharmaceutical brand name manufacturers to prolong their patent royalties, 'evergreening' is rarely mentioned explicitly by judges in patent protection cases. The term usually refers to threats made to competitors about a brand-name manufacturer's tactical use of pharmaceutical patents (including over uses, delivery systems and even packaging), not to extension of any particular patent over an active product ingredient. This article focuses in particular on the 'evergreening' potential of so-called 'linkage' provisions, imposed on the regulatory (safety, quality and efficacy) approval systems for generic pharmaceuticals of Canada and Australia, by specific articles in trade agreements with the US. These 'linkage' provisions have also recently appeared in the Korea-US Free Trade Agreement (KORUSFTA). They require such drug regulators to facilitate notification of, or even prevent, any potential patent infringement by a generic pharmaceutical manufacturer. This article explores the regulatory lessons to be learnt from Canada's and Australia's shared experience in terms of minimizing potential adverse impacts of such 'linkage evergreening' provisions on drug costs and thereby potentially on citizen's access to affordable, essential medicines

Effectiveness of ophthalmic solution preservatives: a comparison of latanoprost with 0.02% benzalkonium chloride and travoprost with the sofZia preservative system

<p>Abstract</p> <p>Background</p> <p>Although in vitro and in vivo laboratory studies have suggested that benzalkonium chloride (BAK) in topical ophthalmic solutions may be detrimental to corneal epithelial cells, multiple short- and long-term clinical studies have provided evidence supporting the safety of BAK. Despite the conflicting evidence, BAK is the most commonly used preservative in ophthalmic products largely due to its proven antimicrobial efficacy. This study was designed to characterize the antimicrobial performance of two commonly used topical ocular hypotensive agents that employ different preservative systems: latanoprost 0.005% with 0.02% BAK and travoprost 0.004% with sofZia, a proprietary ionic buffer system.</p> <p>Methods</p> <p>Each product was tested for antimicrobial effectiveness by <it>European Pharmacopoeia </it>A (EP-A) standards, the most stringent standards of the three major compendia, which specify two early sampling time points (6 and 24 hours) not required by the <it>United States Pharmacopeia </it>or <it>Japanese Pharmacopoeia</it>. Aliquots were inoculated with between 10⁵and 10⁶colony-forming units of the test organisms: <it>Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans </it>and <it>Aspergillus brasiliensis</it>. Sampling and enumeration were conducted at protocol-defined time points through 28 days.</p> <p>Results</p> <p>BAK-containing latanoprost met EP-A criteria by immediately reducing all bacterial challenge organisms to the test sensitivity and fungal challenges within the first six hours while the preservative activity of travoprost with sofZia did not. Complete bacterial reduction by travoprost with sofZia was not shown until seven days into the test, and fungal reduction never exceeded the requisite 2 logs during the 28-day test. Travoprost with sofZia also did not meet EP-B criteria due to its limited effectiveness against <it>Staphylococcus aureus</it>. Both products satisfied United States and Japanese pharmacopoeial criteria.</p> <p>Conclusions</p> <p>Latanoprost with 0.02% BAK exhibited more effective microbial protection than travoprost with sofZia using rates of microbial reduction, time to no recovery for all challenges and evaluation against EP-A criteria as measures. The rapid and complete reduction of all microbial challenges demonstrates that antimicrobial activity of latanoprost with 0.02% BAK exceeds that of travoprost with sofZia preservative system in these products and provides a more protective environment in the event of contamination and subsequent exposure to microorganisms during use.</p

Patient organization involvement and the challenge of securing access to treatments for rare diseases:Report of a policy engagement workshop

Plain English summary Patients with rare diseases often help to develop new treatments for their conditions. But once developed, those treatments are sometimes priced too high for many patients to access them. We became aware that this is a problem in the course of a social science research project that examines the place of rare diseases in health policy. We therefore organized a two-day workshop to try and understand why this problem occurs and what might be done about it. The people who participated in our workshop were: representatives of rare disease patient organizations, experts in matters of drug regulation and assessment of new health technologies, consultants involved with companies producing treatments for rare diseases, and social scientists researching related issues. The main conclusions to emerge from the discussions were as follows: Problems of access to treatments for rare diseases are not just due to high prices; procedures for regulating, assessing and delivering new treatments also need to be better organized. Patients and patient organizations have much to contribute to this process. However, their resources are often very limited. Consequently, more needs to be done to help them use those resources as effectively as possible. In particular, regulators and healthcare providers need to ensure that their procedures are clear and efficiently managed, so as not to waste patient organizations’ time and money. Clearer guidance is needed on what patient organizations can do to provide evidence of the effectiveness of new drugs. Insights gained in tackling rare diseases might also be applicable to common disorders. Finally, the consequences of Brexit for UK policies on rare diseases urgently need to be assessed. Abstract Since the enactment of orphan drug legislation in the USA, Europe and several other countries, an increasing number of treatments for rare diseases have been developed and many of them been approved for marketing. However, such treatments tend to be priced very high, and access to effective treatments remains a major challenge for patients with rare diseases – despite active involvement of patients and their support organizations in various stages of basic and applied research and commercial development. In order to allow patients to benefit from treatments proved effective for their diseases, we need to better understand why this challenge persists, and what steps might be taken to address it. To that end, we organized a policy-engagement workshop, bringing together individuals and organizations with direct experience of trying to secure access to a treatment for a rare disease along with individuals with relevant expertise in regulatory and commissioning processes for new medicines. With additional input from social scientists who offered different perspectives on the value of patient involvement, the workshop aimed to initiate a dialogue among the participants about how to address the challenge in a sustainable manner. Discussions at the workshop stressed that active involvement of patients is as valuable in the regulatory and commissioning processes as in the research and development of new medicines. However, it also highlighted certain risks and costs associated with such involvement. These include the costs of adjusting to abrupt changes in regulatory and commissioning processes, and the risk of being perceived as too close to commercial interests. To optimize use of scarce resources and ensure continuing active involvement, such risks and costs need to be better managed. Participants also noted that, owing to advances in genomic technologies, common diseases are also becoming divided into rare sub-categories, which are equally eligible for orphan drug designation. Consequently, involvement of wider patient communities beyond rare disease communities will be critical for continuing discussions about patients’ involvement in regulatory and commissioning processes, and to consider how patients and their support organizations can best work with other stakeholders – including companies, regulators and policymakers – to ensure access to effective medicines

Pharmaceutical research in paediatric populations and the new EU Paediatric Legislation: an industry perspective

A large proportion of medicines used in children are prescribed off-label, and children have often been denied access to new or innovative medications. Because such situation is unethical, the need to obtain paediatric information for medicines used in children seems nowadays a matter of consensus on a global basis. Based on this, it was clear in EU, like what has happened in the US, that there was a need for a legal obligation for Pharmaceutical Companies to perform studies. This new European Paediatric Regulation that entered into force in 2007 opens a new era of European drug regulatory history and will offer a major opportunity to improve children's health through advancements in research by providing a new framework for evaluating the efficacy and safety of medicines for children. But, paediatric development remains challenging and the hurdles of conducting research in paediatric population are numerous. The article presents the new European Paediatric Regulation, illustrates its rationale through paediatric psychopharmacology, and discusses some of its consequences on paediatric research from an industry perspective. Recommendations for further international collaboration are also suggested to make global paediatric development plans